Large efforts are currently underway funded by the NIH, the Gates foundation, and the WHO, to reduce the spread of HIV transmission by developing an effective microbicide. The CAPRISA trial with tenofovir gel is the first demonstration of prophylaxis against HIV and HSV using a topical microbicide. Because protection increased with increasing adherence, and because intravaginal rings (IVRs) may increase adherence, the development of a ring formulation of tenofovir is an urgent global priority. We have developed a platform technology for the sustained local release of antivirals that has led to the only FDA approved sustained-release antiviral device: the Vitrasert(R). We propose to adapt this technology to develop a sustained release IVR formulation for tenofovir. The original aim of this proposal was to develop IVRs to release acyclovir, since genital herpes co-infection significantly increases the rate of HIV transmission. The disappointing results of the Partners trial with oral acyclovir and the recent positive results for tenofovir from the CAPRISA trial in the prevention of both HSV and HIV suggested to us that tenofovir is a better drug on which to concentrate our efforts. We discussed this change with program officers at the DAIDS and with our Scientific Review Officer. It was the consensus that acyclovir should be replaced by tenofovir. In phase 1 of this proposal, we demonstrated preliminary efficacy and pharmacokinetics of acyclovir in a murine model. With work funded elsewhere, we have also completed safety and pharmacokinetic studies with rings releasing tenofovir. Efficacy studies with tenofovir rings in the macaque model are ongoing. We also fabricated human-sized rings releasing both tenofovir and acyclovir and have demonstrated safety of these rings in a sheep model. In phase 2 we propose to the work necessary to obtain an IND from the FDA for the tenofovir IVR. The specific aims of this 3 year AT-SBIR are: 1, to establish a GMP manufacturing facility for intravaginal rings; 2, to manufacture a lot sufficient to carry out pre-clinical studies under GMP; 3, to perform animal trials necessary to support an Industry Sponsored Investigational New Drug Application (IND); and 4, to manufacture lots of tenofovir drug-eluting intravaginal rings under Good Manufacturing Procedures sufficient for large scale Phase 3 clinical trials The milestones for successful completion of this proposal are the granting of an IND from the FDA, and the production of clinical trial lots sufficient for pivotal trials.